Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis

Camps, Montserrat; Rückle, Thomas; Ji, Hong; Ardissone, Vittoria; Rintelen, Felix; Shaw, Jeffrey P.; Ferrandi, Chiara; Chabert, Christian; Gilliéron, Corine; Françon, Bernard; Martin, Thierry; Gretener, Denise; Perrin, Dominique; Leroy, Didier; Vitte, Pierre-Alain; Hirsch, Emilio; Wymann, Matthias P.; Cirillo, R; Schwarz, Matthias; Rommel, Christian

doi:10.1038/nm1284

Cited by 716 publications

(692 citation statements)

References 39 publications

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“…The results confirmed that 9AA treatment results in downregulation of p110g levels. In addition, whereas p110g expression Small molecule targeting AKT/mTOR, PI3K, NF-jB and p53 pathways C Guo et al was previously shown to be limited to cells of hematological origin (Camps et al, 2005;Rommel et al, 2007), we found that p110g is expressed in tumor cell lines of various origins, including RCC, fibrosarcoma (HT1080), colon carcinoma (HCT116). We tested different 9AA doses and lengths of treatment and observed downregulation of p110g expression as early as 4-8 h after treatment with at least 5 mM 9AA (Figure 1 and data not shown).…”

Section: P110g Expression Is Decreased In Tumor Cells Treated With 9aamentioning

confidence: 56%

“…Under normal conditions p110g expression is largely restricted to the hematopoietic system, although it can also be detected in endothelium, heart and brain (Camps et al, 2005). Genetic inactivation of p110g allows normal development to adulthood, but causes defects in the immune system (Ru¨ckle et al, 2006).…”

Section: Small Molecule Targeting Akt/mtor Pi3k Nf-jb and P53 Pathwmentioning

confidence: 99%

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9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

et al. 2009

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Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs. The small molecule 9-aminoacridine (9AA) and its derivative, the antimalaria drug quinacrine, have selective toxicity for tumor cells and can simultaneously suppress nuclear factor-jB (NF-jB) and activate p53 signaling. To investigate the mechanism underlying these drug activities, we used a combination of twodimensional protein separation by gel electrophoresis and mass spectrometry to identify proteins whose expression is altered in tumor cells by 9AA treatment. We found that 9AA treatment results in selective downregulation of a specific catalytic subunit of the phosphoinositide 3-kinase (PI3K) family, p110c. Further exploration of this observation demonstrated that the mechanism of action of 9AA involves inhibition of the prosurvival AKT/ mammalian target of rapamycin (mTOR) pathway that lies downstream of PI3K. p110c translation appears to be regulated by mTOR and feeds back to further modulate mTOR and AKT, thereby impacting the p53 and NF-jB pathways as well. These results reveal functional interplay among the PI3K/AKT/mTOR, p53 and NF-jB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by a single small molecule such as 9AA could result in efficacious and selective killing of transformed cells.

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Section: P110g Expression Is Decreased In Tumor Cells Treated With 9aamentioning

confidence: 56%

Section: Small Molecule Targeting Akt/mtor Pi3k Nf-jb and P53 Pathwmentioning

confidence: 99%

9-Aminoacridine-based anticancer drugs target the PI3K/AKT/mTOR, NF-κB and p53 pathways

et al. 2009

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“…Studies with these inhibitors support the following conclusions: (1) p110a is the primary insulin responsive PI3K in adipocytes and myotubes and is the major PI3K associated with insulin receptor substrate-1 (IRS-1) , (2) p110b contributes to the pathogenesis of arterial thrombosis (Jackson et al, 2005), (3) p110g mediates inflammation in a model of rheumatoid arthritis (Camps et al, 2005) and (4) p110d is an essential component of neutrophil directional movement (Sadhu et al, 2003) and plays a role in cell proliferation of acute myeloid leukemia (Sujobert et al, 2005).…”

Section: Introductionmentioning

confidence: 88%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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“…Therefore, PI3K has become the subject of impressive pharmacological efforts as a target to treat inflammatory disease 5,99 . PI3K inhibitors (for example, AS605240) have shown therapeutic effects in mouse models of rheumatoid arthritis 100 and systemic lupus erythematosus 101 , in which the compounds attenuated the migration of neutrophils and lymphocytes, respectively, into inflamed tissue.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%